It is currently estimated that some five million Americans suffer from congestive heart failure (CHF), a condition of abnormally low cardiac output. More than one million of these afflicted persons are under age 60. An increasing rate of CHF sufferers may be regarded as a sign of progress in the field of cardiology, since it stems in large measure from saving the lives of heart attack victims and patients with other heart problems. But many of the survivors are left with CHF, in which a markedly reduced cardiac output leads to an inability of the heart to maintain the body""s need for oxygen-rich blood circulation. As many as 40 percent of CHF patients are at risk of sudden death.
Another fourteen million Americans are diabetic and forty million more exhibit hypertension (persistent elevated blood pressure). A considerable percentage of patients with diabetic neuropathy, hypertension and other pathologies affecting the nervous system are also at higher risk of sudden death.
Diseases such as CHF, hypertension and diabetes are characteristically associated with an increased autonomic cardiovascular drive (see, e.g., Blood Pressure 1998; Suppl 3:5-13). In addition, increased autonomic cardiovascular drive has been associated with myocardial infarction, cardiac transplantation, tetraplegia and anxiety disorders (Circulation 1996; 93:1043-1065, Bio Psychol March 1998; 47(3):243-63). xe2x80x9cTonexe2x80x9d is the output that emanates from the central nervous system via sympathetic and parasympathetic efferent nerves. The overall xe2x80x9cdrivexe2x80x9d depends on the balance between inhibitory (parasympathetic or vagal) and excitatory (sympathetic) tone and the responsiveness of the organ of interest to that tone. Responsiveness, in turn, depends on the receptor""s properties as well as on the intrinsic functional or anatomic properties of the responding organ. An enhanced autonomic drive, independent of the underlying condition, greatly increases the risk of poor cardiovascular outcomes. It follows that targeting the underlying autonomic imbalance in congestive heart failure, hypertension and diabetes may not only be pathophysiologically sound but may also lead to better outcomes (Juilius, Blood Press 1998; Suppl 3:5-13).
As with any medical therapy, before a therapy is prescribed it is important to identify which patients are at increased risk. For CHF, research has established markers that identify patients at increased risk of sudden death from an imbalance between the sympathetic and parasympathetic systems. Results from a large multi-center trial established that baroreflex sensitivity and heart-rate variability are both predictors of mortality with CHF patients, and when combined, increase the predictive value (Lancet 1988:351:478-484). Similar studies have shown a predictive value of heart rate variability with diabetes (Circulation 1996;93:1043-1065).
The simplest measure of heart rate variability expresses the reciprocal of heart rate (R-R interval) and calculates a standard deviation of all normal beats (SDNN) over a period of time. The baroreflex sensitivity (BRS) is a marker of the capability to reflexly increase vagal activity and to decrease sympathetic activity in response to a sudden increase in blood pressure. It provides a more focused measure of autonomic control than heart rate variability. BRS is calculated from measurement of the rate-pressure response to intravenous phenylephrine.
Treatment strategies for CHF employ methods to decrease the excitatory or sympathetic drive, and/or to increase the inhibitory or parasympathetic drive. The results of clinical trials on two beta-blocker drugs demonstrate the efficacy of decreasing the sympathetic drive for such treatment. The clinical studies confirm earlier reports from dog study models of CHF treated with beta-blockers, that the drugs block the effects of adrenaline which is over-produced in CHF patients. Heart experts suspect that many symptoms of CHF occur as an overreaction of the body to some type of heart-muscle damage. The body misinterprets the situation and reacts as though severe dehydration or serious bleeding were the cause of the lowered blood flow. To stimulate the heart, the body produces more adrenaline, which makes the heart work harder. Deaths were reduced by 35% among patients given the beta-blockers Carvedilol or Metoprolol (Prog. cardiovascular Dis. January-February 1999; 41(4)301-312, which states that beta-blockers should be considered the standard of care for mild-to-moderate heart failure). Unfortunately, beta-blockersxe2x80x94the older versions of which are relatively inexpensivexe2x80x94have side effects that prevent many patients from tolerating this mode of therapy.
Mild exercise has also been demonstrated to improve the sympathetic-parasympathetic balance for CHF patients. In a recent randomized study of 99 patients, Belardinelli reported (Circulation Mar. 9, 1999; 99(9):1173-1182) an 18% mortality in the exercise group compared to a 41% mortality in the non-exercise patient group. This clinical study confirms protective benefits of exercise training in dogs with simulated CHF (Circulation February 1994; 89(2):548552). Heart rate variability (SDNN) also improved by 74% in the dog study, suggesting an improved sympathetic-parasympathetic balance. Although beneficial, exercise is initially risky for the CHF patient until an improved balance of the sympathetic-parasympathetic system can be obtained. Exercise can trigger a heart attack or other adverse cardiac events in patients with unstable CHF. It is essential to monitor the patient closely during the first four to eight weeks of exercise. Even aside from the risk, initiating and maintaining an exercise program is difficult for CHF patients, because of patient fatigue and shortness of breath associated with the disease.
A cardiac defibrillator may be implanted to protect the CHF patient against sudden death upon an event of cardiac fibrillation, but its effect on long term survival is limited (Circulation Dec. 1, 1995; 92(11):3273-3281). The device (as well as the implant procedure) is relatively expensive, and does nothing to correct the underlining imbalance between the sympathetic and parasympathetic systems.
It is a principal aim of the present invention to provide improved methods of treating patients who suffer disorders as a result of increased autonomic cardiovascular drive, including but not limited to CHF, diabetes and hypertension. These improved methods seek to relieve the underlying autonomic imbalance between inhibitory (parasympathetic) and excitatory (sympathetic) tone.
The methods of this invention involve increasing the inhibitory response of the parasympathetic or vagal system. The approach is to stimulate the cardiac branch of the vagus nerve. The protective role of vagal stimulation in the chronic dog CHF model has been reported (Circulation Research 1991;68:1471-1481). Prior to vagal stimulation, 100% of the dogs in the study were at risk of sudden death. After vagus nerve stimulation, only 10% remained at risk, versus 87% of a control group of dogs. The report states that the decrease in heart rate from vagal stimulation is an important but not always essential protective mechanism. The electrophysiological effects secondary to the vagally mediated antagonism of the sympathetic activity on the heart are likely to play a major role. In addition, vagal activity may have antagonized the vasoconstrictor effect of the sympathetic activity by acting on norepinephrine release and also by a direct vasodilatory effect.
Kamath reported on the neurocardiac responses to vagoafferent electrostimulation in eight patients with vagal stimulation for the control of epilepsy (Pace 1992, Vol 15, 1581-1587). These patients were chronically stimulated on the cervical branch below the cardiac branch; therefore, the effects are presumed to be central to the brain. The patients were randomized into High Level and Low Level stimulation groups. Those in the High Level stimulation group had a statistically significant improvement in the LF:HF peak power ratio (an expression of sympathetic dominance) as compared to the Low Level stimulation group, which had no improvement. Although slow and indirect response was elicited, these studies indicate that stimulation of the vagus nerve below the superior cardiac branch can have a long term beneficial effect on the balance of the sympathetic/parasympathetic system. The studies in dogs and humans demonstrate the feasibility of using vagus nerve stimulation to provide the heart with adequate parasympathetic support to promote natural healing.
The present invention, in one of its implementations, provides vagal stimulation to the left vagus nerve above the cardiac branch or on the vagus cardiac branch at a rate determined to limit the upper heart rate of the patient to a physiologically safe limit, such as 100-150 beats-per-minute (BPM). The stimulation is commenced whenever the BPM exceed a predetermined threshold, such as 90 BPM. The rate of cardiac vagus stimulation has an inverse effect on the heart rate. The stimulation rate may be experimentally determined and appropriately adjusted to achieve a particular heart rate for each patient during a treadmill test. For example, vagus nerve stimulation at 6 Hz may be determined to reduce the resting heart rate to 60 BPM. The physician might initiate the treadmill exercise and determine that by programming the vagus nerve stimulation rate to 4 Hz, the heart rate will be limited to about 100 BPM. Each of the vagal stimulation rates should be verified to assure that they do indeed result in the desired heart rate for each particular patient.
An alternative to the above method of limiting the upper heart rate is to sense the heart rate and to stimulate the vagus nerve only when the heart rate exceeds a specified threshold; for example, 100 BPM. Here again, the stimulation rate is experimentally determined by a treadmill test of the patient, to limit the heart rate to the 100-150 BPM range. Alternatively, the stimulation rate is automatically adjusted to maintain the rate within a specified range.
Another alternative method of the invention to limit upper heart rate is to synchronize the VNS to the P or R wave of the patient""s EKG, and deliver a burst delayed from the synchronizing signal. The right vagus nerve is preferred for stimulation because it is more responsive to synchronized heart pacing, but the stimulation may be applied instead to the left vagus nerve. The burst is preferably approximately 100 msec in duration. The stimulation rate, burst duration, and delay from the synchronization point is programmed to limit the heart rate within a desired range; for example, 100 to 150 BPM. Exemplary values are VNS pulses delivered at a rate of 65 Hz, and the burst delayed 100 msec from the P wave. The heart rate should be monitored and burst mode parameters, specifically burst frequency, should be automatically adjusted to protect the patient from patterns which could produce a heart rate lower than desired.
The present invention provides left or right cardiac vagal stimulation at a rate determined to limit the heart rate 30-45% below the resting heart rate to allow the heart muscle additional time to rest and allow increased capillary blood flow and increased growth of capillary vessels. Since slowing the heart rate to allow time for the heart muscle to heal and to stimulate capillary growth will affect the patient""s exercise tolerance (i.e., the exercise heart rate will be limited by the vagus stimulation rate), it is desirable to maximize the amount of time the heart rate can be slowed without impacting the patient""s ability to function during normal daily activities. Preferably, then, the patient is stimulated only when at rest, and most preferably, when asleep. In any event, when a metabolic need for increased heart rate is indicated, the vagus stimulation is ceased or reduced sufficiently to allow the patient""s normal heart rate to progress to within the upper rate limit range, such as to a programmed level of from 100 to 150 BPM. Of course, it will be understood that patients with CHF are not likely to be engaging in much, if any, strenuous activity.
Each of these methods should employ safety software to prevent stimulation at a frequency that reduces the heart rate below a physiologically safe level. The software should be designed to discriminate against electrical interference that might be interpreted as a fast cardiac signal. This type of discrimination is commonly used in implantable cardiac pacemakers and defibrillators. The VNS rate limit is tailored by programming for each individual patient.
The stimulator preferably incorporates a metabolic need sensor to detect a metabolic need for increased blood flow through higher heart rate. Examples of a suitable sensor include an activity sensor to detect physical activity by the patient (such as an accelerometer), an O2 saturation sensor, a temperature (central venous blood, or physiology) sensor, a respiration (or minute ventilation) rate sensor, a Q-T interval sensor, and so forth. The metabolic need sensor is arranged and adapted to inhibit or otherwise control the vagus stimulation rate to avoid limiting the heart rate to an inappropriately low level in circumstances of patient exercise or activity, which may even be very slight such as getting up from a chair or slow walking. Alternatively or additionally, the stimulator may be programmed to adjust the target heart rate to a higher ventricular rate upon sensing patient activity, so the patient will receive the benefit of a higher heart rate under conditions of exercise.
Subject to approval by the physician, and appropriate programming, the patient may be given some limited control over the therapy. To that end, an external magnet may be made available to the patient to allow initiating stimulation or inhibiting stimulation. The impanted device may be programmed to assume a different heart rate target when activated by a magnet.
Also, the device may be programmed to commence different heart rate targets during local daytime and nighttime hours.